Immune-mediated Engagement of T Regulatory Cells with Tumor Cells Results in Trogocytosis and Tumor Cell Killing.

Erbe, A. K.; Feils, A. S.; Gao, A.; VandenHeuvel, S.; Boyenga, S.; Hampton, A.; Heck, M.; Zaborek, J.; Spiegelman, D.; Tsarovsky, N.; Hoefges, A.; Pieper, A. A.; Carlson, P. M.; Felder, M.; Patel, R. B.; Gillies, S. D.; Heaton, A.; Morris, Z.; Dinh, H. Q.; Rakhmilevich, A. L.; Sondel, P. M.

doi:10.64898/2025.12.11.693807

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bioRxiv · 10.64898/2025.12.11.693807

Immune-mediated Engagement of T Regulatory Cells with Tumor Cells Results in Trogocytosis and Tumor Cell Killing.

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Abstract

Despite advances in treatment, >50% of patients with advanced melanoma are unresponsive to current therapies. Using the B78-D14 melanoma model (GD2+/MHC-I-/MHC-II+), we can cure mice with a regimen that includes radiation therapy (RT) in combination with immunocytokine (IC; anti-GD2 monoclonal antibody linked to IL-2) while establishing immunological memory. We interrogated the role of T cells in the antitumor and memory responses following RT+IC. We show a requirement for CD4, but not CD8 T cells, to achieve both the initial and memory responses. Upon IC-induced cell-cell contact, subsets of CD4 T cells, including Foxp3 T regulatory cells, trogocytose GD2 from tumor cells, acquire cytotoxic granules, and kill tumor cells. These results were confirmed using human tumor cell lines. These findings reveal that CD4 T regulatory cells, upon immunologically-induced binding to tumor cells, can trogocytose tumor antigens and directly kill tumor cells, redefining their potential role in antitumor immunity.

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Erbe, A. K., Feils, A. S., Gao, A., VandenHeuvel, S., Boyenga, S., Hampton, A., Heck, M., Zaborek, J., Spiegelman, D., Tsarovsky, N., Hoefges, A., Pieper, A. A., Carlson, P. M., Felder, M., Patel, R. B., Gillies, S. D., Heaton, A., Morris, Z., Dinh, H. Q., Rakhmilevich, A. L., Sondel, P. M.. 2025-12-15. Immune-mediated Engagement of T Regulatory Cells with Tumor Cells Results in Trogocytosis and Tumor Cell Killing.. https://doi.org/10.64898/2025.12.11.693807

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